Cytomegalovirus (CMV) is a widespread herpesvirus in the human population, with between 0.2 and 2.2% of the infant population becoming infected in utero and another 8-60% becoming infected during the first six months of life (Reynolds et al. (1973) New Engl. J. Med. 289:1). Although CMV infections are most commonly subclinical, CMV-induced sensorineural hearing loss and fatal cytomegalovirus infections (“cytomegalic inclusion disease”) are important public health problems. Moreover, CMV is one of the more common opportunistic infections associated with Acquired Immune Deficiency Syndrome (“AIDS”) and frequently produces disease, with recurrent infection occurring in HIV-positive individuals, typically taking the form of retinitis or ulcerative lesions in the colon and esophagus, and occasionally producing extensive necrotization of the bowel with a grave prognosis (Rene et al. (1988) Div. Dis. Sci. 33:741; Meiselman et al. (1985) Gastroenterology: 88:171). Cytomegalovirus (CMV) infection is the major infectious cause of mental retardation and congenital deafness. CMV is also responsible for a great deal of disease among the immunosuppressed, producing general and often severe systemic effects in patients with AIDS, in organ transplant recipients who have been iatrogenically immunosuppressed, and in bone marrow transplant patients.
It is clear that cytomegalovirus infections are a significant human health problem. Therefore, it is desirable to develop prophylactic and therapeutic methods and compositions to prevent cytomegalovirus infection and/or inhibit recurrent infectious outbreaks from persistent latent infections, particularly for treating CMV retinitis, CMV mononucleosis, and related CMV pathology in human patients.
One approach that has been used to treat herpesvirus infections is to inhibit CMV viral DNA replication. For example, viral DNA replication can frequently be inhibited by agents that inhibit virally-encoded DNA polymerase. The most notable examples of such inhibitors of viral DNA polymerase are acyclovir, ganciclovir, citrusine-I, and the acyclic guanosine phosphonate (R,S)-HPMPC (Terry et al. (1988) Antiviral Res. 10:235; Yamamoto et al. (1989) Antiviral Res. 12:21). However, these compounds are not completely selective for viral thymidylate synthetases or DNA polymerases and therefore can disadvantageously cause inhibition of host DNA replication at high doses. Moreover, the development of mutant viruses which are resistant to the inhibitory effects of these compounds have been reported, and appear to result from mutations in the viral DNA polymerase (Coen et al. (1982) J. Virol. 41:909; Coen et al. (1980) Proc. Natl. Acad. Sci. (U.S.A.) 77:2265; Larder et al. (1987) EMBO J. 6:169). Thus, while CMV infections, such as CMV retinitis, can be initially treated with foscarnet and ganciclovir, after a period of time CMV replication and progression of the pathological viral infection recurs.
Passive immunization with antibodies (e.g., immune globulin) has been tested in combination with ganciclovir for therapeutic efficacy in humans. Such antibody preparations are obtained from the serum of donors, who possess a high antibody titre to the virus as a result of an earlier infection. One disadvantage of such conventional antibody preparations is the limited number of suitable donors and the poor reproducibility or quality of the various preparations, including potential contamination with pathogens and pathogenic viruses. Unfortunately, the use of intravenous immune globulin in combination with ganciclovir apparently does not produce significantly improved efficacy as compared to ganciclovir treatment alone (Jacobson et al. (1990) Antimicrob. Agents and Chemother. 34:176). The safety and pharmacokinetic profiles of anti-cytomegalovirus monoclonal antibodies are discussed in Aulitzky et al. (1991) J. Infect. Dis. 163:1344 and Drobyski et al. (1991) Transplantation 51:1190. However, none of the reported human anti-CMV monoclonal antibodies have been shown to possess significant therapeutic efficacy in treating CMV infections (e.g., retinitis) in humans.
Attempts to use recombinantly produced hCMV glycoproteins as a subunit vaccine to provide protective immunity against hCMV infection and pathogenesis have not proven to be effective, but remain candidates for additional evaluation.
Thus, there exists a need in the art for effective methods and compositions for inhibiting human cytomegalovirus replication, attenuating CMV virulence in vivo, neutralizing CMV virions, and for preventing and treating human cytomegalovirus infections, and especially CMV infections in preborns, newborns, and immunosuppressed patients such as AIDS patients. For example but not limitation, a suitable attenuated human CMV vaccine which elicits satisfactory immunoprotection against CMV infection is needed in the art. The present invention fulfills these and other needs.